Irritable bowel syndrome (IBS) is a syndrome which causes chronic symptoms (e.g., abdominal pain, feeling of fullness and the like), bowel movement disorders (diarrhea, constipation and the like), defecation-trouble, straining and the like, due to functional abnormality of lower digestive tracts, mainly the large intestine, despite of the absence of organic disorders such as inflammation, tumor and the like, and is classified based on the conditions of bowel movement into diarrhea-predominant IBS, constipation-predominant IBS and alternating IBS which alternately repeats diarrhea and constipation. IBS is a disease which has a relatively high frequency occupying from 20 to 50% of bowel disease patients who take medical advices by visiting hospitals, is predominant in female because its male to female ratio is 1:2 regardless of the human race, and has high prevalence rate in the younger generation. Since mental stress is strongly concerned in its morbid states, it is regarded as a stress somatic disease and it is said that stress management is important for the improvement of symptoms. Actually, it is known that abnormal digestive tract movements are significantly accelerated and symptoms are worsen when an emotional stress is applied to IBS patients. In addition, since the symptoms continue, it is apt to form a vicious circle in which anxiety is increased in the patients so that the symptoms further worsen.
As the drug therapy of IBS, an anticholinergic is used for abdominal pain, and a tricyclic antidepressant for the improvement of pain threshold value reduction in digestive tracts, and an anti-diarrheal drug, a drug for controlling intestinal function and the like in the case of diarrhea and a saline cathartic and the like in the case of constipation for the improvement of bowel movement disorders, but these are merely a replacement therapy and their effects are not clear too. There is polycarbophil calcium as an agent from which effects can be expected for both diarrhea and constipation, which adjusts hardness of feces by becoming a gel in the intestines, but exerts very limited effects because not only there is a feeling of fullness at the initial stage of its administration but also it requires time for expressing the effects. Anxiolytics and antidepressants are used when anxiety and tension are considerably increased due to stress, but they are administered at a dose lower than the dose in the psychiatric region, so that there is a case in which the mental symptoms are not improved or a case in which these are improved but they do not show their effects on bowel movement disorder. Anxiolytics are effective for diarrhea and abdominal pain in some cases, generally among the symptoms of IBS, but there is a tendency that their effect on constipation is hardly expressed.
There are a 5-HT3 receptor antagonist alosetron and a 5-HT4 receptor agonist tegaserod as agents which have been drawing attention in recent years, and they are used in the diarrhea-predominant and constipation-predominant respectively. These agents improve bowel movement by regulating movement of intestines, and the expression of effect is quick. However, though alosetron shows a relatively high improving rate of from 40 to 60% for abdominal symptoms and diarrhea, constipation occurs in 30 to 35% of the patients and it causes ischemic colitis (including mortal cases) as a serious side effect, so that its use is limited (Non-patent Reference 1). In addition, it cannot be said that the effect of tegaserod on the constipation-predominant is sufficient, and there is a possibility of causing tachyphylaxis (a phenomenon in which resistance is generated when an agent is repeatedly administered within a short period of time).
By the way, when the living body receives a stress, it generates a hypothalamic-pituitary-adrenal system (HPA system) reaction in which adrenocorticotropic hormone (ACTH) is released through the secretion of a stress-related substance from the hypothalamus and subsequent action upon the anterior hypophysis, and the ACTH released into blood secretes corticosterone, and thereby shows various stress responses such as blood pressure increase and the like. As the stress-related substance, corticotrophin releasing hormone (CRH), bombesin (BB)/gastrin releasing peptide (GRP), vasopressin, neuropeptide Y, substance P, neurotensin and the like are known. Secretion of these substances from the hypothalamus is accelerated when a stress is applied to animals. Particularly regarding the CRH, it has been reported that it reinforces ACTH release and large bowel movement when administered to IBS patients (Non-patent Reference 2).
The bombesin/GRP as one of the stress-related substances is a brain-gut peptide and expresses various physiological actions via bombesin receptor. The bombesin receptor is classified into 3 subtypes of BB1, BB2 and BB3/BRS3 (bombesin receptor subtype-3), and as intrinsic ligands of mammals for BB1 and BB2 receptors, neuromedin B and GRP have been identified respectively. It has been reported that GRP and BB2 receptors are present ubiquitously in the brain, digestive tracts and the like, but GRP is markedly increased in amygdala and hypothalamus when a stress is applied to an animal (Non-patent Reference 3). In addition, it has been reported also that a BB2 receptor antagonist inhibits increase of ACTH when administered into the cerebral ventricle in a restraint stress-added rat (Non-patent Reference 4), but there are no reports on the concern of peripheral GRP and BB2 receptor in stress reactions.
As the role of the GRP/BB2 receptor in the digestive tract functions, it has been reported that it enhances the contraction in isolated human and rabbit ileum longitudinal muscle specimens (Non-patent References 5 and 6), and enhances the water secretion in guinea pigs in the coexistence of vasoactive intestinal peptide (VIP) (Non-patent Reference 7). However, there are no reports on its action on defication and its examination using a BB2 receptor antagonist.
As the BB2 receptor antagonist, a peptide compound (RC-3095) represented by the formula (I) is known (Non-patent Reference 8 and Patent reference 1).
[In the Formula, Me Means Methyl.]
Since the bombesin/GRP also has a function as a cell growth factor and expression of the GRP/BB2 receptor is increased in various cancer cells of lung cancer, prostate cancer and the like, efficacy of RC-3095 has been reported by a large number of antitumor tests (Non-patent References 9 to 11). Currently, clinical tests of RC-3095 are carried out on various solid carcinomas, but there are no reports on the action of this compound upon the digestive tract functions, and there are no reports also on the efficacy and applicability of BB2 receptor antagonist for IBS.
As other BB2 receptor antagonists, for example, a compound represented by a formula (II) (BIM 26226, Non-patent Reference 12 and Patent Reference 2),
[In the Formula, Me Means Methyl]
1-ethyl-3-[methylene-(3′,5′-di-tert-butyl-4′-hydroxyphenyl)]-5-(2′-carboxybenzyloxy)oxyindole (CP-70030; Non-patent Reference 13 and Patent Reference 2), 1-(3′,4′-dichlorobenzyl)-5-bromo-spiro-[imidazoline-4,3′-azaindoline]-2,2′,5-trione (CP-75998; Non-patent Reference 13 and Patent Reference 2), (S)-3-(1H-indol-3-yl)-N-[1-(5-methoxypyridin-2-yl)cyclohexylmethyl]-2-methyl-2-[3-(4-nitrophenyl)ureido]propionamide (PD 176252; Non-patent Reference 14 and Patent Reference 3) and the compounds described in Patent References 1 to 8 and the like have been reported. However, efficacy and applicability of BB2 receptor antagonist for IBS are not reported also in these references.
Also, (2E)-3-[5-(4-nitrophenyl)-2-furyl]-1-phenyl-2-propen-1-one (CAS Registry No. 38898-76-9; Non-patent Reference 15) has been reported as an intermediate for synthesizing a compound having an antibacterial action, but its BB2 receptor antagonism and efficacy and applicability for IBS are not reported therein.
In addition, 2-chloro-5-nitro-N-(4-{[2-(pyridin-3-yl)piperidin-1-yl]sulfonyl}phenyl)benzamide (CAS Registry No. 393834-75-8),
N-(4-chloro-2-methylphenyl)-2-[(3,4-dimethoxyphenyl)phenylsulfonyl]amino]acetamide (CAS Registry No. 335208-47-4), and
N-[3-(1,3-benzothiazol-2-yl)-6-isopropyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl]-3,5-dimethoxybenzamide (CAS Registry No. 486396-92-3) are known as catalog compounds, but their BB2 receptor antagonism and efficacy and applicability for IBS have not been reported.    Non-patent Reference 1: American Journal of Gastroenterology, (USA), 2003, vol. 98, p. 750-758    Non-patent Reference 2: Gut, (England), 1998, vol. 42, p. 845-849    Non-patent Reference 3: The Journal of Neuroscience, (USA), 1998, vol. 18, p. 4758-4766    Non-patent Reference 4: Life Sciences, (Holland), 2002, vol. 70, p. 2953-2966    Non-patent Reference 5: Gastroenterology, (USA), 1991, vol. 100, p. 980-985    Non-patent Reference 6: Neurogastroenterology and Motility, (England), 1997, vol. 9, p. 265-270    Non-patent Reference 7: Annals of the New York Academy of Science, (USA), 2000, vol. 921, p. 420-424    Non-patent Reference 8: The Prostate, (USA), 1994, vol. 25, p. 29-38    Non-patent Reference 9: Cancer, (USA), 1998, vol. 83, p. 1335-1343    Non-patent Reference 10: British Journal of Cancer, 2000, vol. 83, p. 906-913    Non-patent Reference 11: Cancer, (USA), 2000, vol. 88, p. 1384-1392    Non-patent Reference 12: Regulatory Peptide, (Holland), 1994, vol. 53, p. 165-173    Non-patent Reference 13: Bioorganic & Medicinal Chemistry Letters, (Holland), 1992, vol. 2. p. 333-338    Non-patent Reference 14: Bioorganic & Medicinal Chemistry Letters, (Holland), 1998, vol. 8, p. 2589-2594    Non-patent Reference 15: Il Farmaco, (Holland), 2001, vol. 56, no. 10, p. 919-927    Patent Reference 1: International Publication No. 92/09626    Patent Reference 2: International Publication No. 91/9102746    Patent Reference 3: International Publication No. 92/07830    Patent Reference 4: International Publication No. 98/07718    Patent Reference 5: JP-A-7-258081    Patent Reference 6: International Publication No. 00/09115    Patent Reference 7: International Publication No. 02/40469    Patent Reference 8: International Publication No. 02/40475